Signaling in the integrated stress response (ISR). ER stress, nutrient deprivation, oxidative stress, and hibernation are all associated with elevated eIF2α phosphorylation. The first two activate known eIF2α kinases, whereas the others act through unknown mechanisms. Phosphorylation of this factor inhibits translation of most mRNAs, leading to a decline in protein synthesis rates. Paradoxically, the translation of the transcription factor ATF4 is increased, increasing the transcription of specific target genes under conditions of ER stress. Expression of one of these target genes, GADD34, may set the stage for the resumption of mRNA translation after ER stress is resolved.